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New Oral anticoagulants
1. An Updated Review of
Target-Specific Oral Anticoagulants Used in
Stroke Prevention in Atrial Fibrillation
Diya Saleh
Registrar, BPT
2. Question #1
An 82 year old man. What is the chance he has
atrial fibrillation?
A.
B.
C.
D.
1%
5%
10%
25%
3. Prevalence of Diagnosed AF
Stratified by Age and Sex
12.0
10.0
Women
Men
11.1
10.3
9.1
8.0
7.3
6.0
5.0
4.0
3.0
1.7
2.0
0.0
0.1 0.2 0.4
<55
0.9
7.2
5.0
x-axis = %
y-axis = # of
men/women
3.4
1.7
1.0
55-59
60-64
65-69
70-74
75-79
80-84
> 85
# Women
530
310
566
896
1498
1572
1291
1132
# Men
1529
634
934
1426
1907
1886
1374
759
Go AS, JAMA. 2001 May 9;285(18):2370-5. Pub Med PMID: 11343485
4. Question #2
A 46 year old. What is his lifetime risk of
developing AF?
A.
B.
C.
D.
1%
5%
10%
25%
5. Incidence of AF
Lifetime Risk for AF at Selected Index Ages by Sex
Index Age, yrs
Men
Women
40
26.0% (24.0 – 27.0)
23.0% (21.0 – 24.0)
50
25.9% (23.9 – 27.0)
23.2% (21.3 – 24.3)
60
25.8% (23.7 – 26.9)
23.4% (21.4 – 24.4)
70
24.3% (22.1 – 25.5)
23.0% (20.9 – 24.1)
80
22.7% (20.1 – 24.1)
21.6% (19.3 – 22.7)
1 in 4
Men & women
>40 Years
will develop AF
Lifetime risk if
currently free
of AF
Lloyd-Jones DM, et al. Circulation. 2004 Aug 31;110(9):1042-6. Pub Med PMID: 15313941.
6. Question #3
68 year old female with atrial fibrillation and no
other co-morbidities. How would you classify
her stroke risk?
A. Low
B. Moderate
C. High
7. CHA2DS2-VASc
2009 Birmingham Schema Expressed as a Point-Based Scoring System
Risk Factor
Congestive heart failure/LV dysfunction
Hypertension
Age ≥ 75 y
Diabetes mellitus
Stroke/TIA/TE
Vascular disease
(prior myocardial infarction, peripheral artery disease, or aortic plaque)
Age 65-74 y
Sex category
(i.e. female gender)
LV = left ventricular; TE = thromboembolism
Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Chest. 2010 Feb;137(2):263-72. Pub Med PMID: 19762550.
Score
1
1
2
1
2
1
1
1
8. Question #3
68 year old female with atrial fibrillation and no
other co-morbidities. How would you classify
her stroke rate per year?
A.
B.
C.
D.
1%
2%
3%
4%
9.
10. Question #4
78 year old male with atrial fibrillation and
hypertension (CHADS2 score = 2 [4% stroke rate per
year]). What is his annual major bleeding rate?
A.
B.
C.
D.
E.
1%
2%
3%
5%
10%
12. Bleeding Risk Scores in AF
ATRIA
HAS-BLED
HEMORR2HAGES
Anemia1
3
Hypertension4
1
Hepatic10 or
disease2
1
1
Severe renal disease2
3
Abnormal Renal5 or
1
1
Ethanol abuse
1
Age ≥75 yrs
2
Stroke
1
Malignancy
1
Any prior hemorrhage
1
Bleeding
1
Older Age (>75 yrs)
1
Hypertension3
1
Labile INR8
1
Reduced platelet number
1
Elderly (>65 yrs)
1
Rebleeding12
2
Drugs9 or
1
1
Hypertension4
1
Anemia13
1
Genetic factors14
1
Excessive fall risk15
1
Stroke
1
1.
2.
3.
4.
5.
6.
8.
9.
10.
11.
12.
13.
14.
15.
Liver
function6
Hemoglobin <13 g/dl men; <12 g/dl women
Estimated glomerular filtration rate <30 ml/min or dialysis-dependent
Diagnosed hypertension
Systolic blood pressure >160 mmHg
Presence of chronic dialysis or renal transplantation or serum creatinine ≥200 mmol/L
Chronic hepatic disease (eg cirrhosis) or biochemical evidence of significant hepatic derangement (eg bilirubin 2 x upper limit of normal, in
association with aspartate aminotransferase/alanine aminotransferase/alkaline phosphatase >3 x upper limit normal, etc.)
Unstable/high INRs or poor time in therapeutic range (eg <60%)
Concomitant use of drugs, such as antiplatelet agents, non-steroidal anti-inflammatory drugs, or alcohol abuse etc.
Cirrhosis, two-fold or greater elevation of AST or APT, or albumin <3.6 g/dl
Platelets <75,000, use of antiplatelet therapy (eg daily aspirin) or NSAID therapy; or blood dyscrasia
Prior hospitalization for bleeding
Most recent hematocrit <30 or hemoglobin <10 g/dl
CYP2C9*2 and/or CYP2C9*3
Alzheimer's dementia, Parkinson's disease, schizophrenia, or any condition predisposing to repeated falls
Alcohol
Renal
or function11
Apostolakis S, Lane DA, Guo Y, Buller H, Lip GY. J Am Coll Cardiol 2012;60:000–000. 2012 Jul 24. [Epub ahead of print] Online Appendix.
PMID: 22858389.
13. Question #5
78 year old female with atrial fibrillation on
warfarin, hypertension and CHF.
How many times she needs to fall in a year for the
calculated risk of subdural hematoma from falling
to outweigh the stroke reduction benefit of
warfarin?
A.
B.
C.
D.
E.
10 times
30 times
100 times
300 times
600 times
14. Anticoagulation and Risk of Falls in the Elderly –
Putting Matters in Perspective
• The risk of a subdural hematoma from falling is so small.
• A patient with a 5% annual stroke risk from AF would
need to fall 300 times in a year for the calculated risk of
subdural hematoma from falling to outweigh the stroke
reduction benefit of warfarin.
•
•
Man-Son-Hing M, Laupacis A. Anticoagulant-related bleeding in older persons with atrial fibrillation: physicians' fears often
unfounded. Arch Intern Med 2003; 163:1580.
Man-Son-Hing M, Nichol G, Lau A, Laupacis A. Choosing antithrombotic therapy for elderly patients with atrial fibrillation
who are at risk for falls. Arch Intern Med 1999; 159:677.
• Sellers MB, Newby LK. Atrial fibrillation, anticoagulation, fall risk, and
outcomes in elderly patients. Am Heart J 2011; 161:241.
18. Warfarin the underdog!
• Is NOT rat poison
– Rats have evolved (and so
should you…)
• Advantages of warfarin
– Active by the oral route
– Once daily dosing
– Can be monitored
•
•
•
•
Surgeries
Bleeding episodes
Recurrent events
Adherence
– Rapidly-acting antidote
available
– Low cost
19. Problems with Warfarin
•
Food and drug interactions
•
Genetic variation in metabolism
•
dosage adjustments &
freq. monitor with INR
narrow therapeutic window
overlap with parenteral drugs
•
slow onset of action
20. A Cardiologist’s Perspective:
On The Shifting Role of Warfarin
• Warfarin has important limitations that
contribute to underutilization and poor INR
control
– 3 of 4 patients with AF are unprotected or poorly
protected against stroke
• Warfarin will continue to play an important
role:
– For other indications (e.g., prosthetic valves)
– In patients with renal impairment (i.e., CrCl < 15
ml/min)
24. Why Bother To Innovate?
• It’s just too bad that
•
•
•
•
You wouldn’t necessarily get there on time
Comfort would be a significant problem
Forget about “hands free” anything
And who needs seat belts, automatic transmission,
parking/lane change/braking assist, etc., anyway?
25. Why Bother To Innovate?
Safety and convenience are overrated and not worth the money;
you’ll still get from point A to point B… Maybe...
• If you are unlucky enough to crash you will probably survive
• And while you are unlikely ever to be able to replace any broken
parts, well… just get someone else to drive you the next time
26. AN “IDEAL” ANTI COAGULANT
•
•
•
•
•
„Fixed‟ „oral‟ dose
No need for dose adjustment
Wide therapeutic range
Acceptable bleeding risks
No need for monitoring
29. Potential Limitations of New
Anticoagulants
• Antidotes
– None of the newer agents has a specific antidote
•
•
•
•
•
•
Monitoring
Adverse Drug Events
Compliance
Cost
Clinical Trials vs. Actual Clinical Practice
Patient populations not even studied (i.e. Cancer)
30. No blood monitoring is an advantage of
NOACs
but it is also a major disadvantage…
33. Primary Endpoints
Atrial Fibrillation Trials
Study
NOAC
VKA
Outcome
RE-LY
Dabigatran
1.1%
Warfarin
1.7%
RR 0.66
95% CI 0.53-0.82
P < 0.001
superiority
ARISTOTLE
Apixaban
1.3%
Warfarin
1.6%
HR 0.79
95% CI 0.66-0.95
P= < 0.001 Non- I
P= 0.01
Superiority
ROCKET-AF
Rivaroxaban
1.7%
Warfarin
2.2%
HR 0.79
95% CI 0.66-0.96
P = <0.001
Non-Inferiority
34. Major Bleeding
Atrial Fibrillation Trials
Study
NOAC
VKA
Outcome
RE-LY
Dabigatran
3.3%
Warfarin
3.6%
RR 0.93
95% CI 0.81-1.07
P = 0.31
ARISTOTLE
Apixaban
2.1%
Warfarin
3.1%
HR 0.69
95% CI 0.60-0.8
P = < 0.001
ROCKET-AF
Rivaroxaban
5.6%
Warfarin
5.4%
HR 1.04
95% CI 0.90-1.20
P = 0.58
35. Intracranial Hemorrhage
Atrial Fibrillation Trials
Study
NOAC
VKA
Outcome
RE-LY
Dabigatran
0.3%
Warfarin
0.7%
RR 0.40
95% CI 0.27-0.60
P= <0.001
ARISTOTLE
Apixaban
0.3%
Warfarin
0.8%
HR 0.42
95% CI 0.30-0.58
P = <0.001
ROCKET-AF
Rivaroxaban
0.5%
Warfarin
0.7%
HR 0.67
95% CI 0.47-0.93
P = 0.02
36.
37.
38.
39.
40.
41.
42.
43.
44.
45. Meta-analysis of Efficacy and Safety of
New Oral Anticoagulants
Dabigatran, Rivaroxaban, Apixaban vs. Warfarin in AF patients
All cause stroke/SEE
Ischemic and unspecified stroke
Hemorrhagic stroke
Miller CS, Grandi SM, Shimony A, Filion KB, Eisenberg MJ. Am J Cardiol. 2012 Aug 1;110(3):453-60. Pub Med PMID: 22537354..
46. Meta-analysis of Efficacy and Safety of
New Oral Anticoagulants
Dabigatran, Rivaroxaban, Apixaban vs. Warfarin in AF patients
Major bleeding
Intracranial bleeding
GI Bleeding
Miller CS, Grandi SM, Shimony A, Filion KB, Eisenberg MJ. Am J Cardiol. 2012 Aug 1;110(3):453-60. Pub Med PMID: 22537354.
47. Reversal of NOACs
Suggestions for Reversal of New Oral Anticoagulants
Apixaban
Dabigatran
Rivaroxaban
Oral activated charcoal
Yes
Yes
Yes
Hemodialysis
No
Yes
No
Hemoperfusion with
activated charcoal
Possible
Yes
Possible
Fresh frozen plasma
No
No
No
Activated factor VIIa
Unclear
Unclear
Unclear
3-factor PCC
Unclear
Unclear
Unclear
4-factor PCC
Possible
Possible
Possible
PCC: prothrombin complex concentrate, PCCs with normal amounts of VII are known as 4-factor PCCs whilst the products
without VII are 3-factor PCCs
Kaatz S, et al. Am J Hematol. 2012 May;87 Suppl 1:S141-5. Pub Med PMID: 22473649.
48. Laboratory Testing New Oral Agents
Lab
Tests
Useful Dabigatran Rivaroxaban
Lab Test
Strong
ECT
Chromogenic
Anti-Xa
TT
Apixaban
Chromogenic
Anti -Xa
aPTT, PT
aPTT
Weak
PT / INR
ECT: Ecarin clotting time
Palladino M et al A J Hem 2012;87 Suppl:S127-S132
49. Optimal Candidates for New Drugs
Patients who:
•Find INR testing burdensome
•Despite adherence to provider
recommendations, have low ‘time-in-range’
•Can afford (or arrange to get) the new drugs
•Have normal renal function
50. Optimal Candidates for Warfarin
Patients who:
•Have (borderline) renal insufficiency
•Are taking stable dose of warfarin and do not
find INR testing burdensome
•Have access to self-testing machine
•Are concerned about the lack of an evidencebased reversal strategy
51. Choice of Anticoagulant Based on Patient Characteristics?
Characteristic
Drug Choice
Rationale
Mechanical or valvular AF
Warfarin
New agents not studied
Liver dysfunction with elevated
INR
Warfarin
New agents require hepatic metabolism
Poor compliance
Warfarin or nothing
Missed doses of greater consequence with shorter
acting agents
Stable on warfarin
Warfarin
Consider switching at patient request
CrCl < 30 mL/min
Warfarin
Such patients were excluded from trials with new
agents
CrCl of 30-50 mL/min
Rivaroxaban or
Apixaban
Oral Xa inhibitors are less affected by impaired
renal function than dabigatran
Dyspepsia or upper GI complaints
Rivaroxaban or
Apixaban
Dyspepsia in up to 10% given dabigatran
Recent GI bleed
Apixaban
More GI bleeding with dabigatran (150 mg BID) or
rivaroxaban than with warfarin
Recent ischemic stroke on
Warfarin
Dabigatran
Dabigatran (150 mg BID) associated with lowest
risk of ischemic stroke vs warfarin
Recent acute coronary syndrome
Rivaroxaban or
Apixaban
Small MI signal with dabigatran
Poor compliance with BID
regimen or desire for once daily
Rivaroxaban
Only oral agent that is currently once a day
Adapted/modified from Weitz & Gross, Hematology 2012:536-40
52. A Cardiologist's Perspective:
On The Evolving Treatment Paradigm for Stroke Prevention in AF
• Compared with warfarin, each of the 3 new
agents:
– Are at least as effective in preventing
stroke/systemic embolism
– Are associated with less intracranial bleeding
– Are associated with similar or less major bleeding
– Offer greater ease of use
53. Some Final Insane Musings
• Imagine if the novel anticoagulants had been
established therapy for some 6 decades and a new
drug appeared that:
– Was unpredictable in terms of patient therapeutic
response
– Had slow therapeutic onset and offset
– Had a narrow therapeutic window
– Required close monitoring via frequent blood tests
– Required frequent dose adjustment
– Was plagued by drug-drug and drug-food interactions
– Was associated with more intracranial haemorrhage
– Resulted in a 10% increase in mortality
Would anyone in their right mind think it had a chance of getting to
market and, if it did, would anyone prescribe it?
54. • “HAD WARFARIN INTRODUCED INTO THE
MARKET TODAY, THE US FDA WOULD HAVE
REJECTED”
-A FAMOUS CARDIOLOGIST DURING THE ESC
“BUT STILL, WARFARIN REMAINS OUR POOR MAN‟S CHOICE”
JAMA. 2001 May 9;285(18):2370-5.Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, Singer DE.Source Division of Research, Kaiser Permanente of Northern California, 3505 Broadway, 12th Floor, Oakland, CA 94611, USA. axg@dor.kaiser.orgCONTEXT: Atrial fibrillation is the most common arrhythmia in elderly persons and a potent risk factor for stroke. However, recent prevalence and projected future numbers of persons with atrial fibrillation are not well described.OBJECTIVE: To estimate prevalence of atrial fibrillation and US national projections of the numbers of persons with atrial fibrillation through the year 2050.DESIGN, SETTING, AND PATIENTS: Cross-sectional study of adults aged 20 years or older who were enrolled in a large health maintenance organization in California and who had atrial fibrillation diagnosed between July 1, 1996, and December 31, 1997.MAIN OUTCOME MEASURES: Prevalence of atrial fibrillation in the study population of 1.89 million; projected number of persons in the United States with atrial fibrillation between 1995-2050.RESULTS: A total of 17 974 adults with diagnosed atrial fibrillation were identified during the study period; 45% were aged 75 years or older. The prevalence of atrial fibrillation was 0.95% (95% confidence interval, 0.94%-0.96%). Atrial fibrillation was more common in men than in women (1.1% vs 0.8%; P<.001). Prevalence increased from 0.1% among adults younger than 55 years to 9.0% in persons aged 80 years or older. Among persons aged 50 years or older, prevalence of atrial fibrillation was higher in whites than in blacks (2.2% vs 1.5%; P<.001). We estimate approximately 2.3 million US adults currently have atrial fibrillation. We project that this will increase to more than 5.6 million (lower bound, 5.0; upper bound, 6.3) by the year 2050, with more than 50% of affected individuals aged 80 years or older.CONCLUSIONS: Our study confirms that atrial fibrillation is common among older adults and provides a contemporary basis for estimates of prevalence in the United States. The number of patients with atrial fibrillation is likely to increase 2.5-fold during the next 50 years, reflecting the growing proportion of elderly individuals. Coordinated efforts are needed to face the increasing challenge of optimal stroke prevention and rhythm management in patients with atrial fibrillation.PMID: 11343485
Lifetime risk for development of atrial fibrillation: the Framingham Heart Study.Lloyd-Jones DM, Wang TJ, Leip EP, Larson MG, Levy D, Vasan RS, D'Agostino RB, Massaro JM, Beiser A, Wolf PA, Benjamin EJ. Circulation. 2004 Aug 31;110(9):1042-6. Epub 2004 Aug 16.PMID: 15313941 Circulation. 2004 Aug 31;110(9):1042-6. Epub 2004 Aug 16. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Lloyd-Jones DM, Wang TJ, Leip EP, Larson MG, Levy D, Vasan RS, D'Agostino RB, Massaro JM, Beiser A, Wolf PA, Benjamin EJ.Source Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University Feinberg School of Medicine, 680 N Lake Shore Drive, Suite 1102, Chicago, IL, 60611, USA. dlj@northwestern.eduBACKGROUND: Atrial fibrillation (AF) is the most common cardiac dysrhythmia and a source of considerable morbidity and mortality, but lifetime risk for AF has not been estimated.METHODS AND RESULTS: We included all participants in the Framingham Heart Study who were free of AF at index ages of 40 years and older. We estimated lifetime risks for AF (including atrial flutter) to age 95 years, with death free of AF as a competing event. We followed 3999 men and 4726 women from 1968 to 1999 (176 166 person-years); 936 participants had development of AF and 2621 died without prior AF. At age 40 years, lifetime risks for AF were 26.0% (95% CI, 24.0% to 27.0%) for men and 23.0% (21.0% to 24.0%) for women. Lifetime risks did not change substantially with increasing index age despite decreasing remaining years of life because AF incidence rose rapidly with advancing age. At age 80 years, lifetime risks for AF were 22.7% (20.1% to 24.1%) in men and 21.6% (19.3% to 22.7%) in women. In further analyses, counting only those who had development of AF without prior or concurrent congestive heart failure or myocardial infarction, lifetime risks for AF were approximately 16%.CONCLUSIONS: Lifetime risks for development of AF are 1 in 4 for men and women 40 years of age and older. Lifetime risks for AF are high (1 in 6), even in the absence of antecedent congestive heart failure or myocardial infarction. These substantial lifetime risks underscore the major public health burden posed by AF and the need for further investigation into predisposing conditions, preventive strategies, and more effective therapies.
Chest. 2010 Feb;137(2):263-72. Epub 2009 Sep 17.Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ.Source University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, UK. g.y.h.lip@bham.ac.ukBACKGROUND: Contemporary clinical risk stratification schemata for predicting stroke and thromboembolism (TE) in patients with atrial fibrillation (AF) are largely derived from risk factors identified from trial cohorts. Thus, many potential risk factors have not been included.METHODS: We refined the 2006 Birmingham/National Institute for Health and Clinical Excellence (NICE) stroke risk stratification schema into a risk factor-based approach by reclassifying and/or incorporating additional new risk factors where relevant. This schema was then compared with existing stroke risk stratification schema in a real-world cohort of patients with AF (n = 1,084) from the Euro Heart Survey for AF.RESULTS: Risk categorization differed widely between the different schemes compared. Patients classified as high risk ranged from 10.2% with the Framingham schema to 75.7% with the Birmingham 2009 schema. The classic CHADS(2) (Congestive heart failure, Hypertension, Age > 75, Diabetes, prior Stroke/transient ischemic attack) schema categorized the largest proportion (61.9%) into the intermediate-risk strata, whereas the Birmingham 2009 schema classified 15.1% into this category. The Birmingham 2009 schema classified only 9.2% as low risk, whereas the Framingham scheme categorized 48.3% as low risk. Calculated C-statistics suggested modest predictive value of all schema for TE. The Birmingham 2009 schema fared marginally better (C-statistic, 0.606) than CHADS(2). However, those classified as low risk by the Birmingham 2009 and NICE schema were truly low risk with no TE events recorded, whereas TE events occurred in 1.4% of low-risk CHADS(2) subjects. When expressed as a scoring system, the Birmingham 2009 schema (CHA(2)DS(2)-VASc acronym) showed an increase in TE rate with increasing scores (P value for trend = .003).CONCLUSIONS: Our novel, simple stroke risk stratification schema, based on a risk factor approach, provides some improvement in predictive value for TE over the CHADS(2) schema, with low event rates in low-risk subjects and the classification of only a small proportion of subjects into the intermediate-risk category. This schema could improve our approach to stroke risk stratification in patients with AF.Comment inCHA2DS2-VASc risk scheme: not ready for clinical use. [Chest. 2010]Obstructive sleep apnea is a risk factor for stroke and atrial fibrillation. [Chest. 2010]